Background

It is unclear to what extent moderate metabolic perturbations in advance of diabetes are associated with cardiovascular disease (CVD). While it has been proposed that insulin resistance and the consequent hyperinsulinaemia may promote atherosclerosis, has been challenged by observations that insulin can be protective in some animal models [1].
Recent meta-analyses suggested that the association of HOMA-IR and fasting insulin with CVD are probably modest (although based on studies with limited power) [2,3]. The relation between insulin resistance and CVD risk remains particularly unclear in the elderly, even though is this one of the most important patient groups considering population CVD burden.
This study benefitted from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) trial cohort [4,5] to examine the association of HOMA-IR with CVD and all-cause mortality in older people (70-82 years old) with pre-existing CVD or at high risk of CVD, and with in-trial diabetes to verify that HOMA-IR measured propensity to develop diabetes.

Main results

During 3.2 years of within-trial follow-up, 283 out of 5033 participants were diagnosed with diabetes.

HOMA-IR and fasting insulin were both strongly associated with incident diabetes, also after adjustment for CVD risk factors and BMI. Persons in the highest vs the lowest tertile of HOMA-IR had a 4.80 (95%CI: 3.14-7.33, P<0.0001) higher risk of developing diabetes and comparison of the highest with the lowest tertile of fasting insulin yielded a 2.43 (95%CI: 1.65-3.58) higher risk.

Over 8.6 years of follow-up, 1943 persons died (all-cause). When adjusting for randomised treatment and country, HOMA-IR and fasting insulin showed trends towards an inverse association with all-cause mortality. No such association was left after further adjustment for other risk factors. Nor were any trends observed to an association between HOMA-IR or fasting insulin and CHD mortality and all CVD.

Conclusion

Analysis of the PROSPER cohort of older people without diabetes revealed that HOMA-IR and fasting insulin were strongly associated with risk of developing diabetes within the 3.2 years of in-trial follow-up. Interestingly, long-term follow-up (8.6 years) provided no compelling evidence for an association between HOMA-IR and all-cause mortality, CHD mortality and CVD events. These observations suggest that insulin and insulin resistance are unlikely to be important CVD risk factors in elderly people without diabetes.